Yamada K A
Department of Neurology, Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Expert Opin Investig Drugs. 2000 Apr;9(4):765-78. doi: 10.1517/13543784.9.4.765.
Excitatory neurotransmission in the CNS depends heavily upon alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type glutamate receptors. Derangements in AMPA receptor mediated synaptic transmission may be a contributing factor in neurological and neurodegenerative diseases and could be a target for therapeutic intervention. Recently, drugs that positively modulate AMPA receptors have been identified, having differential effects upon certain AMPA receptor subunits and different effects upon physiological properties of AMPA receptors. These drugs facilitate AMPA receptor mediated processes and may have beneficial therapeutic effects. For example, certain AMPA modulators facilitate long-term potentiation, which is considered a cellular mechanism that may be important for memory storage and they also facilitate memory encoding in behavioural experiments. Thus, AMPA modulators might ameliorate memory deficits that occur in dementia, such as Alzheimer's disease (AD). However, AMPA receptor mediated excitotoxicity may occur with excessive AMPA receptor activation which occurs in seizures or ischaemia and positive AMPA modulators could promote neuronal injury in those conditions. Ultimately, the clinical utility of positive AMPA modulators will be dependent upon understanding the role of AMPA receptors in certain neurological disorders, identifying receptor subtypes involved in specific neurological disorders and developing drugs with selective actions upon specific AMPA receptor properties that also possess receptor subtype specificity. Currently available drugs have provided significant insight into the physiology and structural determinants of important AMPA receptor properties and some insight into potential clinical uses as well as potential dangers of such drugs.
中枢神经系统中的兴奋性神经传递在很大程度上依赖于α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）型谷氨酸受体。AMPA受体介导的突触传递紊乱可能是神经和神经退行性疾病的一个促成因素，并且可能成为治疗干预的靶点。最近，已鉴定出对AMPA受体具有正向调节作用的药物，这些药物对某些AMPA受体亚基具有不同的作用，对AMPA受体的生理特性也有不同的影响。这些药物促进AMPA受体介导的过程，可能具有有益的治疗效果。例如，某些AMPA调节剂促进长时程增强，这被认为是一种可能对记忆存储很重要的细胞机制，并且它们在行为实验中也促进记忆编码。因此，AMPA调节剂可能改善痴呆症（如阿尔茨海默病（AD））中出现 的记忆缺陷。然而，在癫痫发作或缺血时发生的过度AMPA受体激活可能会导致AMPA受体介导的兴奋毒性，而正向AMPA调节剂在这些情况下可能会促进神经元损伤。最终，正向AMPA调节剂的临床效用将取决于了解AMPA受体在某些神经疾病中的作用，确定参与特定神经疾病的受体亚型，以及开发对特定AMPA受体特性具有选择性作用且也具有受体亚型特异性的药物。目前可用的药物已经为重要AMPA受体特性的生理学和结构决定因素提供了重要见解，也为这些药物的潜在临床用途以及潜在危险提供了一些见解。
